The present invention relates to the pharmaceutical use of 3,4-dihydroxybenzopyranone compounds possessing aci-reductone functionalities in the treatment or prevention of diseases caused by enveloped viruses, such as the herpes viruses, including herpes simplex virus (HSV) types 1 and 2, mumps, measles, influenza and the like.
One benzopyranone aci-reductone compound was reported to have been synthesized using a lengthy synthetic route by Ghosh, K. C., J. Indian Chem. Co., 24:323, (1947), from a salicylate compound. Reaction with acetoxyacetyl chloride afforded an intermediate compound (93%) which upon reaction with Na in refluxing benzene afforded benzopyranone aci-reductone compound 5 (no yield reported). Attempted repetition of the process described in Ghosh to convert the intermediate compound to benzopyranone acid-reductone 5 were unsuccessful. The benzopyranone aci-reductone 5 compound can be prepared, as described by Schank et al., Chem. Ber., 114:1958 (1981), from 4-hydroxycoumarin.
The chemistry and lipid biology of novel aci-reductones having both vinylogous acid and biologically relevant redox functionalities have been investigated. The vinylogous acid-possessing aci-reductone of formula 1 below may mimic carboxylic acid-containing drugs such as the phenoxyacetic acids of formula 2 owing to their similar pka values as disclosed by Witiak et al., J. Med. Chem., 25:90 (1982). However, during docking to a targeted redox enzyme, 2-hydroxytetronic acid aci-reductone 1, but not phenoxyacetic acid 2, reduce oxidated forms of metals and/or activated oxygen species in the catalytic site. Also, the oxidation of the aci-reductone compound by two successive one electron transfers generates the less water soluble nonionic dione 3 which may have enhanced hydrophobic binding at the active site and/or undergo covalent reaction with neighboring sulfhydro or amino nucleophiles at the more electron deficient 2-one carbon atom. ##STR1##
Previously, it was reported in Mehl et al., Antimicrob. Agents Chemother., 18:269 (1980), that clofibric acid (2, R.dbd.R.sub.1 .dbd.Me, Ar.dbd.p--ClPh) inhibit replication of herpes simplex virus type 1 (HSV-1) in Buffalo green monkey kidney (BGM 70) cells. These studies confirm the antiherpetic activity of the antilipidemic drug clofibrate (clofibric acid ethyl ester) as disclosed in Steinhart et al., Virology, 70:241 (1976). Several other reports describe approaches to antiviral drug development based upon causing alterations of cellular lipid metabolism (Grossberg et al., Progr. Immunobiol. Standard, 5:289 (1972); Grossberg et al., Perspect. Virol., 9:279 (1975)) to produce a defective lipid envelope, or a direct effect on the viral envelope, Majuk et al., J. Virol., 24:883 (1977); Snipes et al., Antimicrob. Agents Chemother., 11:98 (1977). Racemic 2-hydroxytetronic acid 1 (R.dbd.H, Ar.dbd.p--ClPh) exhibits a spectrum of antilipidemic properties different from those of clofibric acid (Kamanna et al., Lipids, 24:25 (1989)).
The use of the benzopyranone compound in an antiaggregatory composition is disclosed in the Witiak et al., U.S. Pat. No. 4,845,121, issued Jul. 4, 1989 to one of the co-inventors herein. These references, however, fail to suggest or mention the antiviral activity of benzopyranone aci-reductone compounds.